The proposal will outline a 5-year research and training plan designed to equip the principal investigator with the tools necessary for his development as an academic physician-scientist. He has completed a rigorous clinical training program in internal medicine and cardiology and has had extensive training in molecular and cellular cardiology. He is now poised for a career in academic medicine, and this program will offer a unique opportunity to foster his development into an independent physician-investigator. The sponsor, Dr. Shaun Coughlin, will directly oversee the project and the career development of the principal investigator. Dr. Coughlin is one of the foremost and highly respected leaders in the field of hemostasis and thrombosis, and work from his laboratory has helped to define the field of protease receptor biology. He is the director of the CVRI at UCSF, and is himself a trained cardiologist who has mentored the development of many young physician scientists. The program will enlist the help of an advisory committee that includes three accomplished academic physician scientists-all division chairmen. The research plan is designed to follow naturally from a body of work started by the principal investigator while a fellow in the sponsor's laboratory. This includes the observation that thrombin signaling in mouse platelets occurs through PAR4. Knockout of the gene encoding mouse PAR4 resulted in a phenotype of abnormal hemostasis and impaired thrombosis in vivo. The proposal describes a plan to 1) use bone marrow transplantation to ask whether specific disruption of thrombin signaling in platelets versus endothelial cells can impair thrombosis or hemostasis in vivo, and 2) to define how disruptions in thrombin signaling can affect thrombosis or hemostasis. The CVRI and the Department of Medicine at UCSF are the ideal settings to carry out the training and the work described in the proposal. There is expertise in nearly every area of biomedical science and excellence in clinical care. The atmosphere is collegial and collaborative, and there are ample opportunities for learning and development. Finally, there is a deep commitment from the institution to the career development of the candidate and a high potential for the principal investigator to succeed in his goals to establish a distinguished independent program and academic career.